Fenofibrate is one of the best options for treating hypertriglyceridemia. In the majority of patients, fenofibrate lowers triglycerides by 24-55% and improves HDL- and LDL-cholesterol. However, the response to fenofibrate is highly variable and currently there are no screening tests to identify poor responders. Genetic and environmental factors may explain the high variability in response. Among Caucasians, we have identified two polymorphisms, one in the apolipoprotein A5 (ApoA5, rs3135506) gene and another detected by genome wide association in the glucose kinase regulatory protein (GCKR, rs780094) gene that predict fasting triglyceride concentrations and response to fenofibrate in a large, pharmacogenetic study (U01HL072524-06). We hypothesize that these genetic markers will be useful for screening patients for response to fenofibrate in clinical practice. Our goal is to replicate findings from the Genetics of Lipid Lowering and Diet Network (GOLDN) study and to confirm that ApoA5 and GCKR predict fenofibrate response in other populations. With ever decreasing genotyping costs and increasing drug expense, we foresee a great potential in developing a feasible gene-based screening test for response to fenofibrate. Toward that goal, we will conduct a 4-week replication and feasibility study to determine whether the effects of ApoA5 and GCKR genetic polymorphisms on fenofibrate (TriCOR(r)145 mg per day) response observed in Caucasians also exist for men and women seeking treatment for dyslipidemia. We will recruit 400 hypertriglyceridemic (>200 mg/dL) individuals, about 29% African American, whose physician has made a decision to treat them with fenofibrate. Specifically, we will (1) recruit patients in Birmingham, AL who are eligible for fenofibrate therapy and who consent to fenofibrate and genotyping;(2) determine whether rs3135506, a functional SNP in the APOA5 gene individually or (3) in combination with GCKR rs1260326, a functional SNP in strong LD with rs780094, predict the triglyceride-lowering response to fenofibrate. Although exploratory in nature, this study is of clinical and public health importance because prediction of drug response among those with hypertriglyceridemia is clinically challenging and fenofibrate prescription costs are large ($90 to $130/patient/month);targeting the responsive patients at the outset will help improve treatment outcomes at a lower cost. If successful, we will propose to conduct a large, randomized trial on the effect of pre-prescription genotyping on fenofibrate response. RELEVANCE: A large number of people have high amounts of blood fats including triglycerides. Even with fenofibrate, one of the best drugs for treating elevated triglycerides, a large number of patients show poor response to therapy. In this study we will test a concept that by assessing the genetic makeup of an individual you can identify those who will get the best benefit and those who will not respond well. The latter could then be treated with other medications that they might respond to better. This could save time and money and improve treatment of elevated blood fats.